Abstract 2051: Precision immune phenotyping from primary tumor and metastatic lesions reveals novel insights into therapeutic intervention in cancer immunotherapy

2020 ◽  
Author(s):  
Andreas Roller ◽  
Claudia Ferreira ◽  
Laura Jarassier ◽  
Astrid Heller ◽  
Gabriele Dietmann ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Therapeutic Intervention ◽  
Primary Tumor ◽  
Metastatic Lesions ◽  
Immune Phenotyping

scholarly journals Targeted next-generation sequencing assays using triplet samples of normal breast tissue, primary breast cancer, and recurrent/metastatic lesions

2020 ◽  
Author(s):  
Toshiaki Akahane ◽  
Naoki Kanomata ◽  
Oi Harada ◽  
Tetsumasa Yamashita ◽  
Junichi Kurebayashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Primary Tumor ◽  
Primary Breast Cancer ◽  
Breast Tissue ◽  
Normal Breast Tissue ◽  
Metastatic Breast ◽  
Normal Breast ◽  
Human Breast ◽  
Metastatic Lesions ◽  
Generation Sequencing

Abstract Background: Next-generation sequencing (NGS) has shown that recurrent/metastatic breast cancer lesions may have additional genetic changes compared with the primary tumor. These additional changes may be related to tumor progression and/or drug resistance. However, breast cancer-targeted NGS is not still widely used in clinical practice to compare the genomic profiles of primary breast cancer and recurrent/metastatic lesions.Methods: Triplet samples of genomic DNA were extracted from each patient’s normal breast tissue, primary breast cancer, and recurrent/metastatic lesion(s). A DNA library was constructed using the QIAseq Human Breast Cancer Panel (93 genes, Qiagen) and then sequenced using MiSeq (Illumina). The Qiagen web portal was utilized for data analysis.Results: Successful results for three or four samples (normal breast tissue, primary tumor, and at least one metastatic/recurrent lesion) were obtained for 11 of 35 breast cancer patients with recurrence/metastases (36 samples). We detected shared somatic mutations in all but one patient, who had a germline mutation in TP53. Additional mutations that were detected in recurrent/metastatic lesions compared with primary tumor were in genes including TP53 (three patients) and one case each of ATR, BLM, CBFB, EP300, ERBB2, MUC16, PBRM1, and PIK3CA. Actionable mutations and/or copy number variations (CNVs) were detected in 73% (8/11) of recurrent/metastatic breast cancer lesions.Conclusions: The QIAseq Human Breast Cancer Panel assay showed that recurrent/metastatic breast cancers sometimes acquired additional mutations and CNV. Such additional genomic changes could provide therapeutic target.

PD-L1 expression in primary clear cell renal cell carcinomas (ccRCCs) and their metastases.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 467-467 ◽  
Author(s):  
Marcella Callea ◽  
Elizabeth M Genega ◽  
Mamta Gupta ◽  
André P Fay ◽  
Jiaxi Song ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Primary Tumor ◽  
Clear Cell ◽  
Predictive Biomarkers ◽  
Primary Tumors ◽  
Metastatic Lesions ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Membranous Staining ◽  
Formalin Fixed

467 Background: Clinical trials evaluating anti-PD-1 and anti-PD-L1 antibodies (Abs) in ccRCC have shown promising efficacy in a subset of patients. Preliminary studies have demonstrated that tumor PD-L1 expression increases the likelihood of benefit with anti-PD-1 Ab, but fails to identify all responders. One potential explanation for these results is that predictive biomarkers are usually evaluated in the primary tumors, which are more readily available; however, biomarker expression in nephrectomy samples may not accurately reflect expression in the metastases that are being targeted by therapy. In this study, we compared PD-L1 expression in a series of ccRCCs and their metastases. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue blocks from 34 primary ccRCCs and corresponding metastases were retrieved. Multiple areas of the primary tumors, including areas of predominant and highest Fuhrman nuclear grade (FNG), were selected for analysis. Slides were immunostained with a mouse monoclonal anti-PD-L1 antibody (405.9A11). The assay was validated using FFPE cell line controls known to be positive or negative for PD-L1 expression by flow cytometry. The presence of tumor cells with membranous staining was assessed. A case was considered positive when any tumor cell positivity was detected. Results: Positive membranous PD-L1 expression in tumor cells was observed in 10/34 (29%) primary ccRCCs. In 3 of these 10 cases (30%), the metastases were negative. In 2 cases the primary tumor was negative but the metastases were positive. In twenty-two cases, both the primary tumor and the corresponding metastasis were negative. The pattern of PD-L1 staining was highly heterogeneous in the primary tumors and was restricted to areas of highest FNG. The staining was more homogeneous in the metastases. PD-L1 expression by the tumor infiltrating immune cells is currently being evaluated. Conclusions: Discordant expression of PD-L1 between the primary tumor and the corresponding metastases was detected in 5/34 (15%) cases, suggesting that accurate assessment of predictive biomarkers for PD-1 blockade in ccRCC might require analysis of metastatic lesions. Analysis of a larger patient cohort is ongoing to confirm these findings.

The Pattern of p14ARF Expression in Primary and Metastatic Human Endometrial Carcinomas

2010 ◽  
Vol 20 (6) ◽  
pp. 993-999 ◽  
Author(s):  
Piotr Olcha ◽  
Marek Cybulski ◽  
Danuta Skomra ◽  
Bogdan Obrzut ◽  
Atanas Ignatov ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Fallopian Tube ◽  
Primary Tumor ◽  
The Other ◽  
Uterine Neoplasms ◽  
Advanced Stage ◽  
Primary Tumors ◽  
Metastatic Lesions ◽  
Protein Immunoreactivity ◽  
Clinicopathological Variables

Objectives:Alterations of p53 pathway (p14ARF/MDM2/p53) play a crucial role in the development and progression of various human neoplasms, including endometrial carcinoma (EC). The aim of the current research was to examine the p14ARF expression pattern in primary ECs and corresponding metastatic lesions.Materials and Methods:We studied 47 primary ECs and corresponding metastatic lesions applying immunohistochemistry and investigated the relationship between p14ARF overexpression and clinicopathological variables of carcinoma as well as TP53 alterations.Results:Protein expression was predominantly nuclear, present in 32 (68%) of 47 primary cases and in 28 (60%) of 47 metastatic lesions. There were seven p14ARF-positive primary tumors showing negative reactivity in the metastatic lesions. On the other hand, 3 cases lacked protein immunoreactivity in the primary ECs but revealed weak nuclear staining in the corresponding metastases. A case of primary cervical adenocarcinoma metastasizing to the lymph nodes showed p14ARF expression both in the primary tumor and the corresponding metastases. A trend was found between the p14ARF expression in primary tumors and the presence of the neoplasms in the fallopian tube (P = 0.063), but none of the other clinicopathological variables of carcinoma was related to protein immunoreactivity in advanced-stage uterine neoplasms. The p14ARF expression in EC metastases was related to the presence of the primary tumor in the fallopian tube (P = 0.036). The p14ARF expression was not associated with unfavorable outcome both in the primary tumors (P = 0.302) and in the corresponding metastases (P = 0.217). There was also no relationship between the p14ARF expression pattern and TP53 pathway alterations.Conclusions:Altogether, the p14ARF protein is expressed in more than half of the primary ECs and metastatic lesions analyzed and is associated with the transtubal dissemination of the primary tumor. The pattern of the p14ARF expression is not associated with the alterations of other TP53 pathway members in advanced-stage human ECs.

scholarly journals Immunoregulatory Monocyte Subset Promotes Metastasis Associated With Therapeutic Intervention for Primary Tumor

2021 ◽  
Vol 12 ◽  
Author(s):  
Takumi Shibuya ◽  
Asami Kamiyama ◽  
Hirotaka Sawada ◽  
Kenta Kikuchi ◽  
Mayu Maruyama ◽  
...  
Keyword(s):  
Lung Metastasis ◽  
Therapeutic Intervention ◽  
Primary Tumor ◽  
Tissue Repair ◽  
Target Cells ◽  
Monocyte Subset ◽  
Local Inflammation ◽  
Cxcr4 Antagonist ◽  
Metastatic Recurrence ◽  
Metalloproteinase 9

Systemic and local inflammation associated with therapeutic intervention of primary tumor occasionally promotes metastatic recurrence in mouse and human. However, it remains unclear what types of immune cells are involved in this process. Here, we found that the tissue-repair-promoting Ym1+Ly6Chi monocyte subset expanded as a result of systemic and local inflammation induced by intravenous injection of lipopolysaccharide or resection of primary tumor and promoted lung metastasis originating from circulating tumor cells (CTCs). Deletion of this subset suppressed metastasis induced by the inflammation. Furthermore, transfer of Ym1+Ly6Chi monocytes into naïve mice promoted lung metastasis in the mice. Ym1+Ly6Chi monocytes highly expressed matrix metalloproteinase-9 (MMP-9) and CXCR4. MMP-9 inhibitor and CXCR4 antagonist decreased Ym1+Ly6Chi-monocyte-promoted lung metastasis. These findings indicate that Ym1+Ly6Chi monocytes are therapeutic target cells for metastasis originating from CTCs associated with systemic and local inflammation. In addition, these findings provide a novel predictive cellular biomarker for metastatic recurrence after intervention for primary tumor.

HER-2 gene amplification in circulating tumor cells (CTCs): Concordance with amplification status in primary breast cancers and metastatic lesions

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e12006-e12006
Author(s):  
R. Yerushalmi ◽  
M. Mishaeli ◽  
D. G. Huntsman ◽  
K. A. Gelmon
Keyword(s):  
Breast Cancer ◽  
Gene Amplification ◽  
Primary Tumor ◽  
Molecular Characteristics ◽  
Fish Analysis ◽  
Breast Cancers ◽  
Metastatic Lesions ◽  
Significant Incidence ◽  
Inappropriate Treatment ◽  
Her 2

e12006 Background: Recent studies have suggested a significant incidence (10%-30%) of discordance in HER-2 expression between metastatic lesions and the primary breast cancer (BC) which can result in inappropriate treatment recommendations. Biopsies of recurrent BC can aid in determining the expression but are often painful, costly, or cause delays in therapy. We initiated a study with the objective to determine and compare the molecular characteristics of the primary tumor, CTCs and metastases to assess whether the assessment of HER-2 gene amplification status in CTCs by FISH analysis could be used to determine treatment. Methods: After consent, patients with metastatic BC were enrolled, peripheral blood was collected (5 cc-10 cc), metastases were biopsied and HER-2 expression was determined. Blood samples were used for the CTC assay. We performed the CTC enrichment assay using a combination of anti CK and anti-EpCAM. The criteria for CTCs were: positive for cytokeratins 8, 18, 19, positive for DAPI and negative for CD45. Slides were scanned for CTCs using the Ariol system. When a CTC was identified the slide was reused for HER-2 FISH staining using the PathVysion HER-2 DNA Probe Kit. Initial attempts of FISH on CTCs took 48 hours to complete; to hasten the process, the second scan for FISH was done only on selected areas and the images for CTCs and FISH analysis were fused to obtain FISH images on a specific CTCs resulting in a 1 hour process. Results: To date 58 samples were collected, 40 of which had CTCs. At present, biopsies are being assessed and compared to the primary lesion in the initial 20 cases. Conclusions: FISH analysis of CTCs is a feasible technique and may be used to assess the specific molecular characteristics of breast cancer. Whether their HER-2 status reflects the metastatic or primary tumor is still unclear but is being determined and may have useful clinical application. No significant financial relationships to disclose.

Predictive values of intratumoral microvascular density (MVD) in the patients (pts) with advanced NSCLC and metastatic colorectal cancer (mCRC) receiving chemotherapy plus bevacizumab

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14618-e14618
Author(s):  
L. Zhang ◽  
W. Jiang ◽  
Y. Zhang ◽  
R. Xu ◽  
C. Qian ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Treatment Response ◽  
Primary Tumor ◽  
Unmet Need ◽  
Correlation Coefficients ◽  
Tumor Shrinkage ◽  
Primary Tumors ◽  
Predictive Values ◽  
Metastatic Lesions ◽  
Computed Tomography Scanning

e14618 Background: The using of bevacizumab (VEGFR inhibitor) combined with chemotherapy represents a most noticeable recent advance in clinical oncology for significantly improving pts’ survival in several tumor types. There is an unmet need for seeking biomarker(s) to predict the treatment response of bevacizumab and identify the pts sensitive to the treatment. Our study was designed to investigate the predictive value of intratumoral MVD in NSCLC and mCRC pts treated with bevacizumab. Method: Sixteen NSCLC (stage IIIB/IV) and 15 mCRC pts who underwent chemotherapy (paclitaxel+carbo for NSCLC and IFL for CRC, respectively) combined with Bevacizumab were included into this study. The paraffin-embedded tumor samples (13/16 NSCLC and all CRC samples were collected from primary tumor) were sectioned and stained immunohistochemically for blood vessel markers (CD34 and CD31) to identify the characteristics of intratumoral vasculature. A computerized image analysis program was used to quantitatively calculate the intratumoral MVD (Yao et al., Clin Cancer Res 2007). Treatment response was evaluated by computed tomography scanning. Results: Two types of blood vessel, undifferentiated (CD31+/CD34-) and differentiated (CD34+), were identified. For the 16 NSCLC pts, a positive correlation was found between the largest tumor shrinkage percentage (evaluate in the primary tumors and metastases) and the total (CD31+) MVD as well as the undifferentiated (CD31+/CD34-) MVD, with Spearman's correlation coefficients equaled to 0.567 (p=0.022) and 0.576 (p=0.019), respectively. However, no significant correlation between tumor shrinkage and MVD was found in CRC pts, in which the treatment response was evaluated in metastatic lesions while the MVD was calculated in primary tumor. Conclusion: This exploratory analysis suggests higher total vessel and undifferentiated vessel MVD appeared to be predictive of bevacizumab treatment advantage for advance NSCLC pts.Our study also indicated that the MVD of primary lesions did not correlate with the treatment response of metastatic lesions in CRC pts. Further studies are needed to verify the predictive role of MVD in the treatment of bevacizumab in NSCLC. [Table: see text]

High concordance of BAP1 and PBRM1 expression in patient-matched primary and metastatic ccRCC tumors.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 507-507
Author(s):  
Amanda Shreders ◽  
Richard Wayne Joseph ◽  
Daniel Serie ◽  
Payal Kapur ◽  
Thai Huu Ho ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Primary Tumor ◽  
Renal Cell ◽  
Clear Cell ◽  
Metastatic Tumor ◽  
Metastatic Tumors ◽  
Cell Renal Cell Carcinoma ◽  
Metastatic Lesions ◽  
High Concordance ◽  
Heterogeneous Tumor

507 Background: Clear cell renal cell carcinoma (ccRCC) is a well-described molecularly heterogeneous tumor. Herein, we assessed the concordance of two of the most commonly mutated genes in ccRCC, PBRM1 (~50%), and BAP1 (~15%), in patient-matched primary and metastatic tumors. Methods: One pathologist (PK) assessed PBRM1 and BAP1 protein expression using immunohistochemistry (IHC) in 99 patients with a primary and at least one metastatic ccRCC tumor available for analysis. All available metastatic tumors were analyzed. Results: A total of 99 patients (48 M0 and 51 M1) had both a primary tumor and at least one metastatic tumor available for analysis. There were a total of 158 metastases with one patient having up to 7 metastases available for analysis. The concordance between primary and patient-matched metastasis was 87% for PBRM1 and 99% for BAP1. We observed a similar concordance between patients with M0 versus M1 disease. Conclusions: While ccRCC is molecularly heterogeneous, PRBM1, and BAP1 are largely concordant between primary and metastatic lesions suggesting that PBRM1 and BAP1 are genetically truncal events in the molecular pathogenesis of ccRCC.

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